Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor
Zoltán Szlávik, Márton Csékei, Attila Paczal, Z. Szabó, Szabolcs Sipos, Gábor Radics, Ágnes Proszenyák, Balázs Bálint, James B. Murray, James Davidson, I‐Jen Chen, P. Dokurno, A.E. Surgenor, Zoe Daniels, Roderick E. Hubbard, Gaëtane Le Toumelin-Braizat, Audrey Clapéron, Gaëlle Lysiak-Auvity, Anne-Marie Girard, Alain Bruno, Maïa Chanrion, Frédéric Colland, Ana-Leticia Maragno, Didier Demarles, Olivier Geneste, András Kotschy
Abstract
Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.